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Nalfurafine (nalfurafine hydrochloride, TRK-820, Remitch®) was launched as an anti-pruritic for uremic pruritus in hemodialysis patients in Japan in 2009. Since the drug is an opioid that mainly binds to κ-receptors and possesses κ-agonistic pharmacological properties and also binds partially, but very weakly, to μ-receptors, the abuse liability of the drug was assessed by using questionnaires in patients enrolled in a clinical trial evaluating the efficacy and safety of the drug. The clinical trial was conducted for up to 52 weeks in patients subjected to regular hemodialysis. End-stage renal disease (ESRD) patients with uremic pruritus (n = 146) were administered nalfurafine 5 μg intravenously after each hemodialysis session. 81 ESRD patients without uremic pruritus served as non-treatment controls. All pruritus patients answered the 3 questionnaires of "the Addiction Research Centre Inventory (ARCI)", "modified Short Opiate Withdrawal Scale (SOWS)", which provides a range of signs and symptoms of opiate withdrawal, and Severity of Dependence Scale (SDS), which measures the dependence potential of the drug. The control patients were tested with the ARCI and modified SOWS questionnaires. There were no significant differences between the nalfurafine group and control group in the ARCI and modified SOWS scales. Thus, no evidence of abuse liability was indicated in the results. Also, no significant differences in the blood pressure, respiratory rate, body temperature and pupil diameter were shown between the two groups.

The purpose of the present study was to observe the psychosocial characteristics of withdrawal from cigarette smoking in comparison with those from caffeine (CAF) and alcoholic (ALC) beverage withdrawal. Twenty-seven healthy volunteers at a medial level of dependence on both cigarettes (nicotine, NCT) and either CAF or ALC, as judged by the DSM-IV-TR criteria for substance dependence, participated in this study. The participants were required to abstain from smoking and either CAF or ALC for 7 days, each one after another, with a 7-day interval. The order of abstinence was counterbalanced among the participants. Psychosocial parameters, including a desire for substances, social activity function, well-being, withdrawal symptoms, and vital signs, were assessed during the withdrawal periods. The study protocol was approved by the Jikei University Review Board. The results indicated that there were no differences in the maximum level of desire for a substance and the influence on social activity function between NCT and other substances during the withdrawal periods. As for withdrawal symptoms, NCT caused a more intensive degree of irritability than CAF or ALC, and a more intensive degree of difficulty concentrating and restlessness than did withdrawal from ALC. However, the subjective well-being questionnaire indicated no differences in these symptoms between NCT and other substances. The present results suggest that there are no significant differences in psychosocial manifestations regarding the difficulty in abstaining from NCT, CAF, and ALC.

A new clinical evaluation form was developed to compare the clinical features of nicotine dependence with those associated with other abused drugs. A new scoring system for clinical evaluation was developed. The form consisted of five scoring items: subjective effects, liking (of drug), withdrawal syndrome, acute psychic and physical disorders, and social disturbance. A preliminary clinical investigation was performed to test the validity of the evaluation form. Study subjects were those showing dependence on nicotine (cigarette smoking, n = 40), alcohol (n = 39), methamphetamine (n = 31), and inhalants (n = 30), who fulfilled the DSM-IV-TR criteria for drug dependence disregarding the state of "a maladaptive pattern of substance use, leading to clinically significant impairment or distress," and gave written informed consent for participation in the study. Nicotine caused a mild or the least degree of subjective effects, liking, and psychic and physical withdrawal symptoms, without any significant social disturbance or acute disorders. With alcohol, liking, withdrawal syndrome, and acute physical disorders were prominent. Methamphetamine produced the most serious acute psychic disorders, with intensive acute physical disorders and psychic withdrawal symptoms. Inhalants were characterized by an intensive degree of acute psychic disorders. As for social disturbance, alcohol, methamphetamine, and inhalants showed more significant influence than nicotine. Our study findings revealed that the clinical features of drug dependence could be evaluated by using the new clinical evaluation form. Further study is required to clarify the clinical features of nicotine dependence compared with those of other drugs of dependence.

Nicotine induces craving, but the degree of craving is believed to be milder than that with other abused drugs. In this article, the neurobiological mechanisms of craving for nicotine and other drugs are reviewed, focusing especially on three factors that can be involved in the development of craving. The first factor is the affective symptoms of withdrawal, the neural basis of which may involve neuroadaptations (desensitization) within the reward systems. Affective symptoms experienced during withdrawal from nicotine are milder than those experienced in withdrawal from other drugs, probably because of its mode of action on the reward systems, which is similar to that of natural rewards. The second factor is the conditioning process, in which environmental stimuli can gain properties of a secondary reinforcer. Nicotine has weak but reliable conditioning effects, and the brain region mediating those effects of nicotine involves the ventral tegmental area. The third factor is a cognitive (memory) process, but little is known about this area.

The stimulating effect of antiparkinsonian drugs, talipexole and bromocriptine, on the striatal postsynaptic dopamine receptors were studied by measuring contralateral rotational behavior in rats. The nigro-striatal dopamine system of rats was degenerated by unilateral injection of 6-hydroxydopamine (6-OHDA, 8 micrograms/rat) into substantia nigra. By subcutaneous administration, talipexole at 0.16 mg/kg and bromocriptine at 10.24 mg/kg induced significantly increased rotational behavior to the contralateral direction to the lesioned side. The onset of the effect was 30 min for talipexole and 90 min for bromocriptine. By intragastric administration, talipexole at 0.4 mg/kg and bromocriptine at 20.48 mg/kg significantly increased the rotational behavior, and the onset of the effect was 60 min for talipexole and 180 min for bromocriptine. Rotational behavior induced by talipexole was suppressed by a D2 antagonist, sulpiride (40 mg/kg, s.c.), but not by a D1 antagonist, SCH23390 (1 mg/kg, s.c.). In contrast, rotational behavior induced by bromocriptine was suppressed by both sulpiride and SCH23390. These results indicated that when the nigrostriatal dopaminergic functions are disrupted, talipexole stimulates the striatal postsynaptic dopamine receptors at much lower doses than bromocriptine. Also it was indicated that the stimulating effect of talipexole is solely mediated by dopamine D2 receptors, whereas the effect of bromocriptine is mediated by both D1 and D2 receptors.

Background: Our previous placebo-controlled, prospective, double-blind study demonstrated that a new opioid ĸ-receptor agonist, nalfurafine hydrochloride, effectively reduced treatment-resistant pruritus in 337 hemodialysis patients. Thus, we designed this study to evaluate prospectively the efficacy, safety, addiction liability, and pharmacokinetics of nalfurafine given orally for 1 year. Methods: This open-label study examined the effects and adverse drug reactions (ADRs) of 52-week oral administration of nalfurafine hydrochloride (5 µg/day) in 211 hemodialysis patients with a treatment-resistant itch. Results: Of 211 patients, 145 completed the study as scheduled. The mean pruritus value assessed by the visual analogue scale was 75.2 mm during the pre-observation period, which decreased significantly to 50.9 and 30.9 mm in week 2 and 52, respectively, indicating a long-lasting efficacy. ADRs occurred in 103 patients (48.8%). Frequent ADRs were insomnia (sleep disturbance, 19.4%), constipation (7.1%) and increased blood prolactin (3.3%), similar to previous reports. Regarding addiction liability, it appeared unlikely that nalfurafine hydrochloride was abused. After the start of treatment, plasma drug levels reached a steady state in week 2 with no apparent tendency of systemic accumulation. Conclusions: Nalfurafine hydrochloride, orally administered at 5 µg/day for 52 weeks to hemodialysis patients, produced a long-term suppression of pruritus without significant safety problems.

The central mechanism mediating the discriminative effects of nicotine was studied using rats. Rats were trained to discriminate subcutaneously administered nicotine at 0.5 mg/kg from saline in a 2-lever operant chamber situation for food reinforcement. 1) Nicotine administered into the lateral ventricle at both 100 micrograms and 120 micrograms substituted for subcutaneously administered nicotine at 0.5 mg/kg. This result indicates that the discriminative effects of nicotine are mediated centrally. 2) Among the drugs, acetylcholine at 0.5-10 micrograms administered into the lateral ventricle and methamphetamine at 5-40 micrograms and dopamine at 1-10 micrograms administered into the nucleus accumbens, none substituted for subcutaneously administered nicotine. These results indicate that the discriminative effects of nicotine differ from those of the above drugs. 3) Nicotine at 100 micrograms administered into the nucleus accumbens almost completely substituted for subcutaneously administered nicotine. In addition, mecamylamine at 180 micrograms administered into the nucleus accumbens attenuated the discriminative effects of subcutaneously administered nicotine. These results suggest that nicotinic receptors in the nucleus accumbens may be involved in the discriminative effects of nicotine. However, further studies are needed, since the nucleus accumbens is regarded not to be a major site of action of nicotine for these effects because of its low susceptibility to nicotine and mecamylamine.

Rationale: Central nicotinic receptors have been reported to be involved in the discriminative stimulus (DS) effects of nicotine. Objectives: The purpose of the present study was to investigate the role of the medial prefrontal cortex (mPFC) and the medial habenular nucleus (mHb) in the DS effects of nicotine. Methods: Substitution tests with nicotine administered into mPFC and mHb were conducted in rats trained to discriminate nicotine (0.5 mg/kg, SC) from saline in a two-lever, food reinforced, operant task. Results: Nicotine (40 µg) administered into mPFC substituted for nicotine (0.5 mg/kg, SC), whereas nicotine administered into mHb did not. Conclusions: Together with our previous study indicating that the nucleus accumbens and the ventral tegmental area are partially involved in the DS effects of nicotine, the present study suggests that mPFC is primarily involved in the DS effects of nicotine.

Ifenprodil is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist which prefers NR2B-containing NMDA receptors to NR2A-containing NMDA receptors. It has been reported that ifenprodil suppresses morphine-induced place preference in mice. In this study, the effects of ifenprodil on the discriminative stimulus effects of cocaine were examined in rhesus monkeys. Five monkeys were trained to discriminate cocaine at 0.25 or 0.5 mg/kg im from saline using a standard two-lever drug-discrimination paradigm under a fixed-ratio schedule of food reinforcement. A single dose of cocaine (0.06-0.5 mg/kg) produced a dose-dependent increase in cocaine-appropriate response, and training doses produced 100% cocaine-lever response in each monkey. Pretreatment with ifenprodil (1 or 2 mg/kg, i.v.) blocked the cocaine-appropriate response when low doses of cocaine were used. The results suggest that NR2B-containing NMDA receptor-mediated mechanisms modulate the discriminative stimulus effects of cocaine in rhesus monkeys.

Nicotine dependence is characterized by weak dependence potential and less ability to produce psychotoxicity and social disturbance. A two-compartment model consisting of "dependence" and "dependence syndrome" was used to clarify clinical features of nicotine dependence. "Dependence" was defined by drug liking. "Dependence syndrome" was defined by a compulsion to take a drug, and drug-induced pathological symptoms (withdrawal syndrome and acute disorders) and social disturbance. Nicotine produced a mild or the least degree of drug liking and withdrawal syndrome, without any significant social disturbance, or acute disorders. Thus, nicotine dependence differed from other forms of drug dependence in that nicotine was not associated with "dependence syndrome". This review also introduced other current topics of nicotine dependence. First, adolescence is regarded as a risk factor for the development of nicotine dependence, whereas the involvement of gender difference (female) in this respect is controversial. Secondly, many smokers feel difficulties in quitting smoking in spite of the weak dependence potential of nicotine, which is known as the "nicotine paradox". Several working hypotheses have been presented to explain this phenomenon. For example, nicotine has relatively strong conditioning effects and/or dependence liability compared with other drugs of abuse. However, further studies should be carried out to clarify clinical characteristics of the "nicotine paradox".

The purpose of the present study was to develop a new clinical evaluation form to compare the clinical characteristics of nicotine dependence with those associated with other drugs of abuse, using a two-compartment model consisting of "drug dependence" and "dependence syndrome". The evaluation form consisted of five scoring items: subjective effects, drug liking, withdrawal syndrome, acute psychic and acute physical disorders, and social disturbance. "Drug dependence" was defined by positive scores on the "drug liking" item. "Dependence syndrome" was defined by positive scores on drug-induced pathological symptoms (withdrawal syndrome, and acute psychic and physical disorders) and social disturbance. The subjects were dependent on nicotine (cigarette smoking) (n = 114), alcohol (n = 101), methamphetamine (n = 90), inhalants (n = 63), and benzodiazepines (n = 39). All subjects met the DSM-IV-TR criteria for drug dependence. Nicotine produced a mild or the least degree of drug liking and withdrawal syndrome, without any significant social disturbance, or acute disorders. The other four drugs produced more intensive degrees of withdrawal syndrome and acute psychic and physical symptoms, with more significant social disturbance than nicotine. The present study indicated that nicotine dependence differed from other forms of drug dependence in that nicotine was not associated with "dependence syndrome".

The purpose of the present study was to develop a new clinical evaluation form to compare the clinical features of nicotine dependence with those associated with alcohol and methamphetamine dependence, using a two compartment model consisting of "drug dependence" and "dependence syndrome". The evaluation form consisted of six scoring items: subjective effects, tolerance, drug liking, social disturbance, withdrawal syndrome, and acute psychic and acute physical disorders. "Drug dependence" was defined by positive scores on the "drug liking" item. "Dependence syndrome" was defined by positive scores on drug-induced pathological symptoms (withdrawal syndrome, and acute psychic and physical disorders) and social disturbance. The subjects were dependent on nicotine (n = 68), alcohol (n = 62), or methamphetamine (n = 55). All subjects met DSM-IV diagnostic criteria for drug dependence. Nicotine produced a mild degree of drug liking and psychic withdrawal symptoms, but did not cause significant physical withdrawal symptoms, acute psychic or physical disorders or social disturbance. Alcohol and methamphetamine produced a moderate degree of drug liking and significant levels of withdrawal syndrome, acute disorders and social disturbance. Thus, in the present study, nicotine dependence differed from other forms of drug dependence in that nicotine was not associated with "dependence syndrome".

The involvement of cerebral regions in the discriminative stimulus (DS) effects of nicotine was studied using rats. Substitution tests with nicotine administered into the medial prefrontal cortex, nucleus accumbens, and ventral tegmental area, all of which are located on the mesolimbocortical dopaminergic neurons, and into the dorsal hippocampus and medial habenular nucleus, which possess high densities of nicotinic cholinergic receptors, were conducted in rats trained to discriminate nicotine (0.5 mg/kg s.c.) from saline solution in a two-lever, food-reinforced, operant task. Nicotine administered into the medial prefrontal cortex substituted for nicotine (0.5 mg/kg s.c.), whereas nicotine administered into the nucleus accumbens and ventral tegmental area partially substituted for sc injected nicotine. However, nicotine administered into the dorsal hippocampus and medial habenular nucleus did not substitute for sc injected nicotine. These results suggest that the medial prefrontal cortex is primarily involved in the DS effects of nicotine, whereas the nucleus accumbens and ventral tegmental area are partially involved.

The purpose of the present study was to develop a new clinical evaluation form to compare the clinical features of nicotine dependence with those associated with alcohol, methamphetamine, and inhalant dependence. The clinical evaluation form consisted of six scoring items: subjective effects, tolerance, liking (of drug), social disturbance, withdrawal syndrome, and acute psychic and acute physical disorders. A preliminary clinical investigation was performed to test the validity of the evaluation form. Study subjects were those showing dependence on nicotine ( n = 25), alcohol ( n = 36), methamphetamine ( n = 11), and inhalants ( n = 6). All subjects met the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) diagnostic criteria for drug dependence, as defined by the Work Group for the chapter "Substance-Related Disorders": M. A. Schuckit, J. E. Helzer, L. B. Cottler, T. Crowley, P. E. Nathan, & G. E. Woody. Nicotine produced subjective effects, tolerance, liking, and psychic withdrawal symptoms, all of which were mild in degree. However, nicotine did not produce social disturbance, physical withdrawal symptoms, or acute psychic or acute physical disorders. With alcohol, acute psychic and acute physical disorders were prominent, and alcohol also produced a moderate degree of influence on various other items that were evaluated. Methamphetamine produced the most serious acute psychic and acute physical disorders with intensive subjective effects. Inhalants were characterized by an intensive degree of acute psychic disorders and subjective effects with mild withdrawal syndrome. Our study findings revealed that the clinical features of drug dependence could be evaluated by using the new clinical evaluation form. Further study is required to clarify the clinical features of nicotine dependence compared with those of other drugs of dependence.

Our recent studies on the reinforcing properties and psychotoxicity of nicotine in rats and rhesus monkeys are introduced. In drug discrimination experiments in rats, the discriminative effects of subcutaneous nicotine were generalized by the nicotine injected into nucleus accumbens or medical prefrontal cortex. In microdialysis in rats, nicotine increased dopamine (DA) and DOPAC at nucleus accumbens and striatum. In self-administration experiments in monkeys, faster infusion speeds resulted in higher intake rates of nicotine and possible development of physical dependence attenuated monkey’s nicotine-seeking behavior. The threshold dose for reinforcing effect of nicotine was found to be 2.5-10 µg/kg.

Since the nucleus accumbens has been hypothesized to centrally mediate the discriminative effects of psychomotor stimulants, the discriminative effects of methamphetamine (MA) as well as dopamine (DA) and noradrenaline (NA) were observed by intracerebral administration of these drugs into the nucleus accumbens in rats discriminating subcutaneous MA from saline. These rats were trained and maintained to discriminate between MA at 0.5 mg/kg, s.c. and saline under a fixed ratio 10 schedule for food reinforcement in a 2-lever operant chamber situation. Guide cannulae were implanted bilaterally into the nucleus accumbens. In the substitution tests, the drug was administered into the nucleus accumbens. MA at 10 micrograms per rat substituted for subcutaneous MA in 4 out of 5 rats but neither DA at 10-40 micrograms per rat (n = 7) nor NA at 10-40 micrograms per rat (n = 4) substituted for subcutaneous MA. On the other hand, the same drugs administered into the nucleus accumbens induced increased spontaneous motor activity as also observed in six other untrained rats. MA, DA or NA alone each at 10 micrograms per rat increased spontaneous motor activity. The discriminative effects of MA are considered to be mediated in the nucleus accumbens of rats. Although DA or NA alone administered into the nucleus accumbens showed similar increasing motor activity effects as those of MA, the discriminative effects of exogenous DA or NA alone administered into the same brain area were different from those of MA in the present experimental condition.

The technical term 'drug dependence' was officially adopted by WHO's Expert Committee on Addiction in 1964. Until this, to describe a state of dependence, terms such as 'poisoning', 'habit', 'ism', and 'addiction' had been used from time to time. Until the 1950's, investigators were mainly focussed on the phenomena of physical dependence. However, once the concept of psychic dependence had been introduced, behavioral and neuropharmacological studies on the modes of drug action that produce psychic dependence were activated and have progressed in the last two decades, and among the points clarified by these studies are the following: 1. The critical drug properties that produce psychic dependence are those of rewarding subjective and reinforcing effects of drugs but these effects are not the properties that produce physical dependence, although the development of physical dependence on particular drugs such as opiates may substantially enhance craving for the drugs. 2. The mesolimbic and mesocortical dopamine systems in the brain and also the N. Accumbens play a primary or at least a partial role in producing the subjective and reinforcing effects of major dependence-producing drugs such as cocaine, opiates, barbiturates, benzodiazepines, and ethanol. 3. Many drugs such as naltrexone, methadone, and some dopamine antagonists and serotonin reuptake inhibitors or antagonists were found to be effective in the pharmacotherapy of the dependence on opiates, cocaine, or ethanol.

The discriminative effects of over-the-counter antitussive syrup containing dihydrocodeine (DHC), methylephedrine (MEP), caffeine (CAF), and chlorpheniramine (CPA) were compared with those of methamphetamine (MA) in a drug discrimination experiment using rats. Rats were trained to discriminate the effects of MA at 0.5 mg/kg SC and saline for food reinforcement under the fixed-ratio 10 schedule in a two-lever operant chamber situation. In substitution testing using a cumulative dose procedure by the subcutaneous route, DHC (4 and 8 mg/kg, expressed hereafter as referred to cumulative dose) or CPA (16-64 mg/kg) individually did not produce MA lever selection. On the other hand, MEP (128 mg/kg) and CAF (64 mg/kg) produced MA lever selection 41.5 and 57.2% of the time, respectively. The complete mixture (16 mg/kg DHC + 32 mg/kg MEP + 33.2 mg/kg CAF + 6.4 mg/kg CPA) produced MA level selection 65.8% of the time. The partial mixture containing only MEP + CAF at the above doses produced MA lever selection 95.6% of the time. Thus, the complete mixture only partially substituted for MA in rats while the partial mixture containing MEP and CAF completely substituted for MA.

To observe the dispositional and functional tolerance to and physical dependence on barbital, the influence of repeated administration of the drug on serum barbital levels, coordinative motion, body weight, and cortical evoked potential was assessed. Rats administered the first dose of barbital showed marked impairment of gross behavior and then loss of the righting reflex. While they were repeatedly treated with barbital for a 4-week period, the CNS depression became weaker and weaker, and loss of the righting reflex was no longer observed. Serum barbital levels after administration of barbital tended to decrease by the 28th day of repeated drug administration. Coordinative motion was markedly impaired after administration of the first dose, but gradually recovered during the repeated administration period. Barbital at 100 mg/kg, i.p., prolonged the latent time of the evoked potential in normal untreated rats but not in tolerant rats. During the withdrawal period, no particular change was observed in the animals' gross behavior. However, body weight loss and shortening of the latent time of the evoked potential were observed at 60 to 72 hours of withdrawal. These results suggest that cortical evoked potential can serve as a useful method for observing tolerance to and physical dependence on barbital.

It is a pleasure for us to introduce the Proceedings of the Satellite Symposium on Nicotine and Alcohol of The 10th Congress of the International Society for Biomedical Research on Alcoholism (ISBRA). The Satellite Symposium was held in Yokohama, Japan, on July 8, 2000. Leading scientists from around the world whose research efforts have focused on nicotine in the tobacco habit and drug dependence participated in the Satellite Symposium. There were 13 papers presented at the meeting, and 12 of those 13 papers are included in this Special Issue. These papers covered most of the major areas of biomedical research on nicotine effect and dependence. The Symposium was structured around three themes: nicotine and brain function, clinical studies on smoking, and biological mechanisms of drug dependence. Both the molecular and genetic mechanisms of, and the differences in clinical features associated with, nicotine dependence, as well as those of other drugs of dependence, were presented and discussed. Both lectures and question-and-answer sessions were stimulating and enlightening. We are grateful to all participants for the excellence of their contributions to the Symposium. I would like to extend our sincere thanks to all the sponsors who generously supported this Satellite Symposium, as well as to Thomas R. Jerrells, Editor-in-Chief of Alcohol, for his valuable advice and cooperation during the publication process of this Special Issue of Alcohol. Because it is the editorial policy of Alcohol that all manuscripts submitted for publication be peer-reviewed before acceptance for publication, we would especially like to extend our thanks to Dr. Jerrells and Janice Jerrells, Managing Editor for Alcohol, for arranging for peer-review of all the manuscripts, as well as to the reviewers who provided their time and expertise to review these manuscripts.

As a method for examining the psychological dependence potential of afloqualone, a centrally acting muscle relaxant, the subjective effects of the drug were studied in 8 healthy male volunteers under the double blind condition. The trial in each subject consisted of a 3-day afloqualone administration session and a 3-day control agent administration session with a 4-day interval between the two sessions. The subjects were hospitalized for the 3 days of each session and treated with oral daily doses of either afloqualone or control agents. In the afloqualone session, 2 capsules containing afloqualone (10 mg each) and 2 placebo capsules, 3 afloqualone capsules and 1 placebo capsule, and 4 afloqualone capsules were administered on the 1st, 2 nd, and 3 rd day respectively.In the control agent session, one capsule containing 5 mg of diazepam and 3 placebo capsules were administered on either the 1st or 3 rd day and 4 placebo capsules were administered on each of the other 2 days. Half of the subjects had the afloqualone session first while the rest had the control agent session first, and in the control agent sessions, half of the subjects received diazepam on the 1st day while the remaining half received it on the 3 rd day. In each session the subjective feelings of the subjects were examined using 4 types of questionnaires given 1 to 11/2 hours after administration. In addition, such psychological tests as the personality, tapping, and Uchida-Kraepelin tests were conducted both prior to and after each administration. As a result, while some statistically significant subjective effects were observed with diazepam, none were found with afloqualone even though the blood levels of the drug were sufficiently high in these subjects. Thus, within the above dose regimen, afloqualone was regarded to have no pharmacological property, productive of psychological dependence in man.

中枢性筋弛緩薬tizanidineにある程度の強化効果があることがサルの実験で観察されたため, ヒトにおける精神依存性の有無を検索する目的で健常人12名を対象として, 本薬およびdiazepamを用いて自覚効果に関する二重盲検比較試験を実施した.その結果, tizanidineは臨床常用1回最大量の3mgおよびその倍量の6mgが服用されても, placeboに比較して明らかな身体的および精神的自覚効果を示さなかった.一方, diazepam 10mgではplaceboやtizanidineに比較して, 有意に高い率で自覚効果に関する肯定回答が得られ, 「ねむい」, 「ぼんやり」等をはじめ, いくつかの項目で中枢抑制効果を示す肯定回答が高率にみられた.またdiazepamでは, その自覚効果を「好ましい」とするもの1例, 「うっとりとしたいい気分」とするもの2例, および「酔った感じ」5例など精神依存性があることを直接示唆する項目への肯定回答もみられた.なお, tizanidineのタッピングや血圧等に対する影響は6mgではdiazepamと同様に観察された.これらのことはtizanidine高用量投与による薬理作用が影響したと考えられる.また血中濃度の測定においても, 6mgでは3mgのときの約4倍の値が得られていることが確認された.

The reinforcing effects of (−)-cathinone, a pharmacologically active ingredient of khat, and 2-amino-1-(2,5-dimethoxy-4-methyl)phenylpropane ((STP) (DOM)), a hallucinogenic psychotomimetic, were studied by intravenous self-administration experiments in rhesus monkeys. Among the experiments described in this paper, the result of continuous self-administration of (−)-cathinone was briefly reported elsewhere. T. Yanagita, Studies on Cathinones, NIDA Research Monograph 27, Proceedings of 41st Annual Scientific Meeting of the Committee on Problems of Drug Dependence, 1979, pp. 326–327.

The drug dependence potential of viloxazine was tested in 5 experiments on rhesus monkeys. In gross behavioral observation of normal monkeys the acute CNS effects of the drug were found to be very weak. Decrement of spontaneous motor activity and occasional eye-closing were observed with single doses higher than 16 mg/kg IV, IM and 128 mg/kg PO, while convulsions and death occured at 64 mg/kg IV and IM. Viloxazine did not suppress the morphine and barbital withdrawal signs in monkeys that had been made physically dependent on these drugs and withdrawal. In the test for physical dependence by repeated administration of the drug at 16 mg/kg IM twice daily for 31 days in normal monkeys, no observable withdrawal sign was developed in the naloxone precipitation and natural withdrawal tests. In intravenous self-administration experiments, a weak reinforcing effect was demonstrated in some monkeys, but the effect was extremely weak. Thus, viloxazine was found to be physical dependence-free and its overall dependence potential was regarded as very low.

The relationship between minimum reinforcing doses and injection speed was investigated by using 2 levels of speeds in experiments on self-administration of cocaine or pentobarbital in 2 crab-eating monkeys each. The experiments were conducted under a fixed ratio (FR) 1 schedule with 30-min time-out after each drug injection, wherein the drugs and saline were made available for alternate 5-day periods. The minimum reinforcing doses at each injection speed were determined by the titration procedure in which the presence or absence of reinforcing effect at a particular drug dose was judged based on comparison of the self-administration rate at that dose with the rate in the preceding saline period. The results showed that the minimum reinforcing doses of cocaine and pentobarbital tended to be higher in inverse proportion to the injection speed of the drugs.

Risk assessment of dependence-producing drugs comprises assessment of two major risks: the risk that a drug is likely to be abused (abuse liability) and the harm that is likely to occur as a consequence of abuse (termed here as harm liability). Important determinants of these risks are the dependence-related pharmacological and toxicological properties of a drug. In this paper, the relationships of the drug properties to the abuse and harm liabilities are described. Next, a scoring system to assess the abuse and harm liabilities is introduced. Finally, an attempt to actually apply this system to several prototypic drugs of abuse and some agonist-antagonist analgesics is explained.

beta-Blocking actions of orally administered Ko 1400 and tiprenolol, new beta-blocking agents, were studied in unanesthetized rats and dogs, using a fall of blood pressure and an increase in heart rate produced by isoproterenol as a measure of beta-receptor activation. Blood pressure was recorded from the aorta of the dog and the caudal artery of rat via indwelling catheter, and heart rate of the dog was recorded by a cardiotachometer triggered by R waves of the lead II electrocardiogram. Mean resting blood pressure was 116 mmHg in rats and 93 mmHg in dogs, and heart rate was 99 beats/min in dogs. Isoproterenol (0.5 microgram/kg) was injected via indwelling venous catheter. Ko 1400, tiprenolol and propranolol inhibited the hypotension and tachycardia induced by isoproterenol at an oral dose level of 2 mg/kg or more. beta-blocking action in these preparations was found to be tiprenolol greater than Ko 1400 greater than propranolol. Pharmacological half life of tiprenolol was longer than that of propranolol, whereas that of Ko 1400 was shorter. No selectivity of beta-blocking actions was observed with all three beta-blockers. These findings are in agreement with the results obtained in isolated atrial and tracheal preparations of the guinea pig.

A nasal catheter was implanted in a monkey which was restrained chronically in a specially designed cage by a freejointed metal arm and harness. Vapors of chloroform, ether or lacquer thinner were sent to the nasal cavity of the monkey through the catheter for a preset time period when he pressed a lever switch which was located on a wall of the cage. Thus, the monkey was able to inhale the organic solvents voluntarily.All six monkeys, two to each agent, took highly concentrated successive doses of the vapors during the daytime and manifested such overt signs of pharmacological effects as ataxia, mydriasis and salivation. Frequent light anesthesia was observed with chloroform. In the course of induction of or recovery from chloroform anesthesia, extreme excitation and hallucinatory behavior were occasionally observed. Two monkeys on chloroform died from suffocation when they were voluntarily self-anesthetized.

Drug depenence liabilty of 5 tricyclic antidepressants, imipramine, imipramine-N-oxide, protriptyline, maprotiline and iprindole, were examined using rhesus monkeys. In gross behavioral observations of acute central nervous system effects in normal monkeys, imipramine, protriptyline, maprotiline and iprindole produced a decrease of awareness, mydriasis, ataxia, tremor and convulsions, but imipramine-N-oxide did not. In cross intravenous self-administration of the drugs with a standard stimulant and saline, no meaningful reinforcing effect on monkeys' drug-seeking behavior was observed with any drug, with the exception of one of the 4 monkeys with iprindole. In the continuous self-administration test, positive self-administration was observed in 2 out of 4 monkeys with imipramine and in one monkey each with imipramine-N-oxide, protriptylin and iprindole. But the self-administration rates were considerably low in comparison with that of principle drugs of abuse and none of these monkeys manifested observable drug effects. No monkey showed positive self-administration of maprotiline. Thus, the amphetamine-like dependence liability was not found in these drugs.

A method has been developed which permits monkeys to self-administer drug solutions, at will, through indwelling intravenous catheters. Psychological dependence on the effects of a drug occurs when a naive monkey voluntarily initiates and maintains self-administration of the drug. If, in addition to psychological dependence, the drug also produces psychotoxicity, either directly or upon abrupt withdrawal, it has a potential abuse liability. In the present study monkeys developed psychological dependence on morphine, codeine, cocaine, d-amphetamine, pentobarbital, ethanol, and caffeine. All of these drugs except caffeine produced psychotoxicity. Monkeys did not develop psychological dependence on nalorphine, morphine-nalorphine mixtures, chlorpromazine, mescaline or physiological saline.

In the drug dependence liability studies, 4 tests were conducted. In the test on acute CNS effects of the drug, normal monkeys did not show any meaningful or physical changes with single oral doses of the drug at 50, 100, 200, 400, and 500 mg/kg.In the test of substitution of Clonixin for morphine in morphine dependent and withdrawn monkeys, single oral doses of the drug at 20, 50, 100, and 200 mg/kg did not suppress morphine withdrawal signs, and thus did not support physical dependence on morphine.In the physical dependence producing test on Clonixin, repeated oral administration of the drug to naive monkeys at daily doses of 100, 200, and 400 mg/kg for 4 weeks did not produce any physical dependence as observed by naloxone tests.In the intragastric self-administration test in drug seeking behavior conditioned monkeys, Clonixin did not positively reinforce the drug seeking behavior. Thus, Clonixin was found to be dependence free.In the teratogenicity test, 2 pregnant monkeys received 30 mg/kg, 2 other pregnant monkeys received 200 mg/kg, and one pregnant monkey received the vehicle alone, daily by gavage for 7 days, from the 23rd to 29th day of pregancy. All fetuses were removed from the uteruses by cesarean section on 59th, 60th or 61 st day of gestation. Detailed examinations of the fetuses revealed no abnormalities at all in external morphological appearance, visceral organs, or skeletal structures.

Sedative-hypnotic type drug dependence liability of B 169, a new anticonvulsant, was studied in rhesus monkeys.In gross behavior observation of acute CNS effects by single oral doses of 500 and 1000 mg/kg, no meaningful effect was observed. At 2000 mg/kg, a slight decrease of spontaneous motor activity and of awareness to outer stimuli was observed one hour after administration. The monkeys, however, reacted normally to man without any impairment of motor function.In the cross physical dependence test in monkeys made, physically dependent on barbital and then withdrawn, the drug did not support the dependence when it was substituted for barbital at single oral doses of 1000 or 2000 mg/kg.When drug seeking behavior conditioned monkeys were allowed to self-administer the drug intragastrically by pressing a lever switch in the cage without time or dose limitation, none of the animals voluntarily ingested the drug. Since they did not initiate self-administration, timer-programmed forced infusion of the drug into the stomach was conducted at a dose regimen of 20 mg/kg/infusion every 6 hours for 2 weeks. Initiation of self-administration was still not observed during or after the programmed administration period. No withdrawal signs were observed at the termination of programmed administration.Thus, B169 was found to be dependence free.

Barbiturate-like drug dependence liability of Calcium N-2-ethylhexyl-β-oxybutyramide semisuccinate (M-2), a new synthetic sedative-hypnotic agent, was studied in rhesus monkeys.In gross behavior observation of acute CNS effects, the compound did not show as strong CNS depressant effects in monkeys as it had in small animals.A physical dependence producing test was conducted by oral administration of the compound 4 times a day, for 4 weeks at dose levels of 100, 200, or 400 mg/kg/day, with 2 naive monkeys for each dose level. At the end of 4 weeks, administration was terminated and a withdrawal test was conducted for 5 days. No meaningful withdrawal signs were observed. On the other hand, oral administration of barbital for 4 weeks produced intermediate to severe grade withdrawal signs in other monkeys.In cross intravenous self-administration of M-2, a CNS stimulant and saline in self-administration conditioned monkeys, the compound did not show drug seeking behavior reinforcing effects at unit doses of 0.25, 1.0, and 4.0 mg/kg/inj..Because of the lack of CNS depressant effects, ability of producing physical dependence and drug seeking behavior reinforcing effects, the potency of dependence liability of M-2 was concluded as practically none.